SUMMARY As HIV+ populations on combination antiretroviral therapies (cART) age, the contribution of neurodegenerative disease to HIV-associated neurocognitive disorders (HAND) is unclear. A number of common pathologic processes are associated with cognitive impairment in aging, including accumulation of abnormal forms of the microtubule-associated protein tau. Tau pathology may occur secondary to amyloid pathology, as occurs in Alzheimer's disease, but may also be seen in a number of amyloid-independent primary tauopathies that affect both neurons and glia. There is a paucity of data on the frequency of age-related tauopathies in cART-era HIV+ populations, as most of these disorders can only be definitively diagnosed at autopsy. The overall objective of this proposal is to address this gap in our understanding, by elucidating the frequency, molecular characteristics, genetic predictors, and clinical manifestations of age-related tauopathies in HIV+ individuals throughout the aging continuum. The overarching hypothesis is that blood brain barrier and vascular abnormalities and chronic neuroinflammation will alter disease manifestations and the relationship of neuropathology to clinical outcomes. A series of 375 well-characterized HIV+ and demographically matched HIV- brains with HIV-associated risks (HCV and substance use) from the Manhattan HIV Brain Bank (MHBB) will be entered into a state-of-the-art pipeline for assessing tau pathologies. We will elucidate the frequency and manifestations of primary age-related tauopathy (PART), aging-related tau astrogliopathy (ARTAG), and chronic traumatic encephalopathy (CTE), providing insight into the effects of neurotropic viral infection on neurodegeneration. Specific aims are: 1a: To perform neuropathologic assessment of HIV+ and HIV- MHBB brains for PART, ARTAG, and CTE, with comparison of the frequency and characteristics of these disorders to that seen in age-matched controls from an autopsy series without HIV or HIV risks; and 1b: to analyze the relationship of PART, ARTAG, and CTE to HIV-associated vascular, inflammatory, and viral pathologies. 2a: To perform molecular analysis of HIV+ and HIV- brains to elucidate regional APP metabolites, and tau levels, isoforms and secondary modifications; and to assess whether molecular signatures of age-related tauopathies in HIV are the same, or differ from, HIV-; and 2b: To perform targeted analysis of genetic predictors for amyloidosis and tauopathies, again to determine the extent to which risk associations are altered by HIV pathologies. 3: To determine the contributions of tauopathies to HIV-related clinical, cognitive, and psychiatric phenotypes. By defining the characteristics and behavioral correlates of age-related tauopathy in HIV, analyses will have relevance to the potential disease-modifying interactions of neurotropic viral infection with a wider spectrum of neurodegenerative disorders, and to nosologies for which early accumulations of amyloid and/or tau define disease categories, and thereby impact clinical trials eligibility.